10-76885239-T-TTA

Variant names:

• chr10-76885239-T-TTA
• rs562756117
• NM_001161352.2:c.*2025_*2026dupTA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001161352.2(KCNMA1):​c.*2025_*2026dupTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 480,628 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.715
• Publications: 0 publications found

Genes affected

KCNMA1 (HGNC:6284): (potassium calcium-activated channel subfamily M alpha 1) This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]

KCNMA1 Gene-Disease associations (from GenCC):

• generalized epilepsy-paroxysmal dyskinesia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• Liang-Wang syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• cerebellar atrophy, developmental delay, and seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00103 (152/147468) while in subpopulation EAS AF = 0.0176 (90/5122). AF 95% confidence interval is 0.0146. There are 1 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.*2025_*2026dupTA		3_prime_UTR	Exon 28 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.*2025_*2026dupTA		3_prime_UTR	Exon 28 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.*2025_*2026dupTA		3_prime_UTR	Exon 28 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.*2025_*2026dupTA		3_prime_UTR	Exon 28 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000286627.10	TSL:1	c.*2025_*2026dupTA		3_prime_UTR	Exon 27 of 27	ENSP00000286627.5	Q12791-5
	KCNMA1	ENST00000640807.1	TSL:1	c.3362+2050_3362+2051dupTA		intron	N/A	ENSP00000491555.1	D5MRH1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 152 AN: 147468 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000679

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.0175

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000895

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 49 AN: 333160 Hom.: 0 Cov.: 5 AF XY: 0.000138 AC XY: 22 AN XY: 159154

African (AFR) AF: 0.000821 AC: 5 AN: 6090

American (AMR) AF: 0.00 AC: 0 AN: 1008

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 6 AN: 2464

East Asian (EAS) AF: 0.0108 AC: 26 AN: 2406

South Asian (SAS) AF: 0.00 AC: 0 AN: 6332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 714

European-Non Finnish (NFE) AF: 0.0000298 AC: 9 AN: 302294

Other (OTH) AF: 0.000267 AC: 3 AN: 11250

GnomAD4 genome AF: 0.00103 AC: 152 AN: 147468 Hom.: 1 Cov.: 30 AF XY: 0.00107 AC XY: 77 AN XY: 71860

African (AFR) AF: 0.00116 AC: 47 AN: 40632

American (AMR) AF: 0.0000679 AC: 1 AN: 14738

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3444

East Asian (EAS) AF: 0.0176 AC: 90 AN: 5122

South Asian (SAS) AF: 0.000421 AC: 2 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000895 AC: 6 AN: 67062

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized epilepsy-paroxysmal dyskinesia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs562756117; hg19: chr10-78644997; COSMIC: COSV54265330; COSMIC: COSV54265330;